Identification of Immune-Related Subtypes and Characterization of Tumor Microenvironment Infiltration in Bladder Cancer.

Mengjia Huang,Junkai Zhu,Yi Chen,Lin Liu,Xinjia Ruan,Tong Jin,Li Xu,Wenxuan Cheng,Fangrong Yan,Liwen Su,Xiaofan Lu,Jialin Meng

doi:10.3389/fcell.2021.723817

Abstract

Tumors are closely related to the tumor microenvironment (TME). The complex interaction between tumor cells and the TME plays an indisputable role in tumor development. Tumor cells can affect the TME, promote tumor angiogenesis and induce immune tolerance by releasing cell signaling molecules. Immune cell infiltration (ICI) in the TME can affect the prognosis of patients with bladder cancer. However, the pattern of ICI of the TME in bladder cancer has not yet been elucidated. Herein, we identified three distinct ICI subtypes based on the TME immune infiltration pattern of 584 bladder cancer patients using the ESTIMATE and CIBERSORT algorithms. Then, we identified three gene clusters based on the differentially expressed genes (DEGs) between the three ICI subtypes. In addition, the ICI score was determined using single sample gene set enrichment analysis (ssGSEA). The results suggested that patients in the high ICI score subgroup had a favorable prognosis and higher expression of checkpoint-related and immune activity-related genes. The high ICI score subgroup was also linked to increased tumor mutation burden (TMB) and neoantigen burden. A cohort treated with anti-PD-L1 immunotherapy confirmed the therapeutic advantage and clinical benefit of patients with higher ICI scores. In the end, our study also shows that the ICI score represents an effective prognostic predictor for evaluating the response to immunotherapy. In conclusion, our study deepened the understanding of the TME, and it provides new ideas for improving patients’ response to immunotherapy and promoting individualized tumor immunotherapy in the future.

Highlights

Bladder cancer is the most common malignant tumor of the urinary system
We identified three distinct immune Immune cell infiltration (ICI) subtypes based on the infiltration patterns of 22 immune cells obtained using the CIBERSORT algorithm and the immune score and stroma score computed by the ESTIMATE algorithm of 584 bladder cancer tumor samples
We identified three ICI subtypes based on ICI and identified three gene clusters based on the differentially expressed genes (DEGs) between the ICI subtypes

Summary

Introduction

Bladder cancer is the most common malignant tumor of the urinary system. It accounts for the highest incidence of genitourinary tumors in China and is the second most common genitourinary malignancy in the United States (Kaufman et al, 2009). According to the histological classification of urinary tract tumors in the 2004 WHO “Pathology and Genetics of Tumors in the Urological System and Male Reproduction Organ,” the pathological types of bladder cancer include bladder urothelial carcinoma, bladder squamous cell carcinoma and bladder adenocarcinoma. Bladder urothelial carcinoma is the most common, accounting for more than 90% of the total number of bladder cancer patients. Most patients with non-muscle invasive urothelial carcinoma receive transurethral resection of bladder tumors and bladder perfusion therapy to prevent recurrence postoperatively. Total cystectomy is often used in patients with muscle invasive urothelial carcinoma, squamous cell carcinoma and adenocarcinoma of the bladder, and partial cystectomy may be used in some patients. 70% of patients relapse after transurethral resection, and Bacillus Calmette-Guerin (BCG) or chemotherapy can reduce the recurrence rate to 25–40%

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